Breast cancer is a heterogeneous disease as demonstrated at a genomic level with the description of different breast cancer subtypes with independent clinical outcome [Cancer Cell 2007; 11: 259-273, Cell 2011; 144: 646-674, Nature 2000; 406: 747-752, Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 10869-10874]. Among them, triple negative breast cancer (TNBC) refers to breast cancer that lacks detectable expression of hormone receptors and no Her2/neu (HER2) gene amplification. In particular, TNBC refers to breast cancer that lacks expression of the estrogen receptor (ER), the progesterone receptor (PR) and the HER2 receptor [Clin. Cancer Res. 2004; 10: 5367-5374].
TNBC is an aggressive form of breast cancer and represents 15% of all breast tumors. By using gene expression analyses it has been classified into seven subtypes with different sensitivities to treatment [J. Clin. Invest. (2011) 121:2750-2767; Clin. Cancer Res. (2013) 19:5533-5540]. Although the identification of these different subtypes represents a major advance in cancer, unfortunately the implementation of this classification for therapeutic purposes is unclear [J. Clin. Invest. (2011) 121:2750-2767]. Therefore, available therapeutic options for patients with TNBC are restricted to standard treatment with chemotherapy, typically based on taxane-, vinca alkaloid- or platinum-based compounds, which are only likely to be effective within the limitations of such chemotherapy in this type of tumor because of their rapid proliferation rates and frequent derangements in DNA repair mechanisms [Nat. Rev. Clin. Oncol. (2010) 7:683-692]. Unfortunately, relapses are frequent, and resistance to the chemotherapeutic agents is often encountered in the metastatic setting and the prognosis of TNBC patients is poor due to the limited therapeutic options and the lack of specific targeted agents [J. Clin. Oncol. (2012) 30(15):1879-1887; Clin. Cancer Res. (2007) 13:4429-4434]. These facts, together with the relatively poor knowledge of the driver molecular alterations present in TNBC, have stimulated identification of aberrant signaling networks that may be pharmacologically attacked in TNBC.
Mithramycin was recently identified as an agent able to sensitize TNBC cells to the antitumoral effect of taxanes, while RNAi screening for agents that enhance paclitaxel activity in TNBC [Breast Cancer Res. (2010) 12:R41]. In this regard, mithramycin was synergistic with paclitaxel in the two paclitaxel-sensitive lines MDA-MB-468 and MDA-MB-231 (average CI value of 0.66 and 0.54, respectively), and in the paclitaxel-resistant cell line HDQP1 (average CI value of 0.87). However, mithramycin and paclitaxel were antagonistic, average CI values significantly >1, in reducing cell viability at high effective drug doses (IC50 and IC25) in the paclitaxel-resistant lines CAL120, SW527 and MT3 (FIG. 4B). Collectively these data indicate that novel drug combinations with paclitaxel can effectively reduce cell viability of select paclitaxel-sensitive and importantly, paclitaxel-resistant TNBC cell lines. Mithramycin is a reversible DNA binding antitumoral antibiotic approved since 1970 by the FDA, although severe side effects have limited its use in the clinic. Recently, promising in vitro and in vivo activity linked to specific modes of action have triggered its clinical evaluation in Ewing sarcoma, lung, esophagus and other chest cancers [ClinicalTrials.gov NCT01610570]. Proteins whose expression is affected by this drug include various protooncogenes, proteins involved in angiogenesis or antiapoptotic processes, p53-mediated transcriptional responses, as well as multidrug resistant gene 1 (MDR-1).
It is therefore the problem of the present invention to provide improved means of preventing and/or treating TNBC, which provides an anti-proliferative, tumor-specific effect, without adverse side effects.